Comprehensive analysis of HIV reservoirs in elite controllers
Authors: Brooke D. Kennedy, Jana Blazkova, Jesse S. Justement, Victoria Shi, M. Ali Rai, Maegan R. Manning, Lauren Praiss, Kathleen Gittens, Paul A. Wender, Sean Patro, Xiaolin Wu, Susan Moir, Tae-Wook Chun
Journal: Journal of Clinical Investigation (2023)

To the Editor: HIV remains an uncurable disease in infected individuals receiving antiretroviral therapy (ART).Despite unparalleled research efforts to find a cure, there is a growing sentiment in the field that complete viral eradication is unlikely with existing therapies.Therefore, an approach involving immune-mediated virologic control without ART represents a realistic goal, even if the HIV reservoir persists (1).In this regard, the ability of some individuals to control HIV replication (i.e., elite controllers [ECs]) illustrates the feasibility of achieving ART-free virologic remission.Prior studies have established that ECs carry low HIV DNA burdens and exhibit robust HIV-specific immune responses (2).However, there are few studies directly comparing the composition and frequencies of HIV reservoirs in ECs with those in chronically infected individuals receiving ART (CAs).We conducted the present study to address this issue.We studied 9 ECs and 22 CAs (Supplemental Table 1 and Supplemental Methods; supplemental material available online with this article; https://doi.org/10.1172/JCI165446DS1).Blood products were obtained in accordance with a protocol approved by the Institutional Review Board of the National Institute of Allergy and Infectious Diseases of the NIH.All participants provided written informed consent.We first compared the composition and size of HIV reservoirs in the EC and CA groups.The levels of total HIV DNA (P < 0.0001), cell-associated HIV RNA (P < 0.0001), intact proviral DNA (IPD) (P = 0.0026), and defective HIV DNA (P < 0.0001) in CD4 + T cells were significantly lower in the EC group compared with those in the CA group (Figure 1, A and B) (2).To assess the replication competency of infected cells, we measured the levels of inducible virion-associated HIV RNA (ivRNA) and replication-competent virus in CD4 + T cells.In contrast to the above data, there was no significant difference in the levels of ivRNA (P = 0.4187) and replication-competent HIV (P = 0.9303) between the two groups (Figure 1C).Three ECs had exceptionally low infectious HIV burdens in their CD4 + T cells.EC-6 and EC-7 had no detectable infectious virus (<1 copy in 245 × 10 6 CD4 + T cells), despite repeated testing.The ratio of intact-to-defective HIV DNA was similar in the EC and CA groups (P = 0.7471; Figure 1D); however, the ratio of IPD to replication-competent virus was significantly lower in the EC group compared with that in the CA group (P = 0.0052; Figure 1D).The frequencies of IFN-γ + and CD107a + IFN-γ + TNF-α + MIP-1β + HIV Gag-specific CD8 + T cells were significantly higher in the EC group compared with those in the CA group (P = 0.0315 and P = 0.0001, respectively; Figure 1E), suggesting that ECs may express sufficient viral antigens.IPD burdens were relatively high in EC-4 and EC-6 (75 and 105 copies/10 6 cells, respectively).Therefore, we conducted longitudinal measurements of ivRNA and IPD (EC-4) and near full-length sequencing of HIV DNA from a sorted CD4 + T subset (EC-6).